System and method for treating various neurological disorders using synchronized nerve activation

ABSTRACT

A neuromodulation system for treatment of physiological disorders. The system includes one or more stimulators for stimulating one or more cranial nerves; one or more detectors configured for detecting a predetermined physiological state; and a control unit that controls nerve stimulation by the one or more stimulators so that it is synchronized with the at least one predetermined physiological state detected by the one or more detectors. A method of neuromodulating a patient for treatment of physiological disorder. The method includes the steps of detecting a predetermined physiological state and applying stimulation to one of the cranial nerves during the predetermined physiological state by one or more stimulators of a neuromodulation system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is the U.S. National Stage of International Application No.PCT/IL2016/051394 filed Dec. 28, 2016, which was published in Englishunder PCT Article 21(2), and which in turn claims the benefit of U.S.Provisional Patent Application No. 62/271,664 filed Dec. 28, 2015.

FIELD AND BACKGROUND OF THE INVENTION

The present invention pertains to the field of treatment of patients whosuffer from neurological disorders such as, but not only, Alzheimer's,Parkinson's, tremor, depression, migraine, headache, peripheral pain,attention deficit disorder (ADD), attention deficit and hyperactivitydisorder (ADHD), sleeping disorders, cognitive dysfunctions and sexualdysfunctions. More particularly, the invention pertains to treatment byactivation of the nerve system using various techniques such as, but notonly, electrical stimulation, sensory stimulations and cognitivestimulations. Treating neurological disorders by activating the nervesystem solely, or in conjunction with medication, is commonly known butis effective only to some extent. A method for synchronized activationsof the central nerve system could synergistically improve theeffectiveness of the treatment and hence, could enable implementing iton therapeutic devices which are more accessible to patients and morecost effective.

The present invention also pertains to the field of providing cognitiveimprovement treatment using nerve stimulation, including treatment ofpatients who suffer from either neurological disorders such as, but notonly, Amnestic Mild Cognitive Impairment (AMCI), Dementia, Alzheimer,Parkinson and Tremor, or healthy individuals who sense cognitivedecline. More particularly, the invention pertains to treatment byactivation of the nerve system using various techniques such as, but notonly, electrical stimulation. Stimulation can be provided during sleepand may include mean to synchronize the nerve stimulus with sleepstages, like, but not limited to, rapid eye movement ((REM) sleep. Inother embodiments, nerve stimulation can be delivered together withother sensory stimulation. A method for simultaneous activation of thenervous system at certain sleep stages could synergistically improve theeffectiveness of the treatment and hence, could enable implementing iton therapeutic devices which are more easy to use to patients and morecost effective. Specifically, nerve stimulation may be applied, but notlimited to, during REM sleep, in which intensive mental and chemicalprocesses occur in the brain.

In one of its embodiments the present invention provides a detectorwhich detects sleep stages. Such a detector includes but not limited toEEG sensors, eye movement sensors, and movement sensors, such asactimetry sensors, ECG analyzers, breath analyzers, and body movementtrackers. The present invention includes a control unit that canactivate nerve stimulation in an afferent direction, during a selectedstage of sleep like REM sleep, or slow wave sleep stage (SWS). Theactivated nerve can be any one of the cranial nerves, including theolfactory nerve (I), the optic nerve (II), oculomotor nerve (III),trochlear nerve (IV), trigeminal nerve (V), abducens nerve (VI), facialnerve (VII), vestibulocochlear nerve (VIII), glossopharyngeal nerve(IX), vagus nerve (X), accessory nerve (XI), and hypoglossal nerve(XII). In a specific embodiment, such nerve can be the auricular branchof the vagus nerve (ABVN) with all its innervations with the greaterauricular nerve, the lesser occipital nerve, and the auriculotemporalnerve.

Non-invasive access to the auricular branch of the vagus nerve ispresented in some embodiments of this invention via a stimulator and oneor more electrodes. These can generally be a type of stimulation devicelocated behind the ear (BTE), in the ear (ITE), in the ear canal (IEC),or completely in the ear canal (CIC), or any combination of these.

Cognitive decline is a major concern for both the aging individual andthe medical community, and in particular early malignant phenomena suchas AMCI (Amnestic Mild Cognitive Impairment), which may represent theearly stage of some form of Alzheimer's. The efforts to halt Alzheimer'sdeterioration include using drugs, mainly cholinesterase inhibitors.

An emerging medical approach is to induce neuro-modulation, usingmethods such as trans magnetic stimulation (TMS), transcranial directcurrent stimulation (tDCS), transcranial alternating current stimulation(tACS), radio electric asymmetric conveyer (REAC), transcranialelectromagnetic treatment (TEMT), deep brain stimulation (DBS), vagalnerve stimulation (VNS) and its non-invasive counterpart, transcutaneousVNS (tVNS). These methods have shown positive effects with other medicalconditions, such as depression, but, in general, they are at apreliminary state in determining if they possess a lasting impact ondementia progression. The invention of the present application isintended to make a contribution in using neuro-modulation to provide animpact in preventing or slowing dementia progression.

SUMMARY OF THE INVENTION

The present invention provides a system and method for treating variousneurological disorders using synchronized activation of the centralnervous system. In some embodiments the activation is in an afferentdirection. The nerve may include one of the following nerves: theolfactory nerve (I), the optic nerve (II), oculomotor nerve (III),trochlear nerve (IV), trigeminal nerve (V), abducens nerve (VI), facialnerve (VII), vestibulocochlear nerve (VIII), glossopharyngeal nerve(IX), vagus nerve (X), accessory nerve (XI), and hypoglossal nerve(XII). For optimal cognitive effect, it is preferable to activate otherbody functions in parallel to nerve activation as indicated for examplein FIG. 8 discussed below. The system of the invention includes variousnerve activators, also sometimes denoted herein as stimulators,including direct nerve activators using electrical stimulator orcognitive activators, and indirect nerve activators such as muscleactivators, or thermal activators and a control unit that controls themultiple nerve activators simultaneously. The stimulators can usevarious stimulation techniques, including, but not limited to,electrical stimulation, mechanical stimulation, thermal stimulation,visual stimulation and audio stimulation. The control unit uses one ormore optimization methods to adjust the parameters of each activator,such as its activation timing, intensity and pattern, i.e. shape of theactivation pattern.

The shape of the pattern is determined by “On” times, “Off” times,positive or negative pulses, and order of pulses. As an example of apattern, a pattern can consist of a positive pulse at intensity I andtime t follow by a negative pulse at intensity I/2 and time t*2. Eachstimulation will included 10 basic pulses with 5t “off” time betweeneach pair of basic pulses.

The present invention also provides a system and method for treatingvarious neurological disorders using activation of the nerve system insynchrony with the different sleep stages. The system of the inventionincludes at least one nerve activator and a control unit that controlsthe at least one nerve activator in synchrony with sleep stages. Thestimulator can use various stimulation techniques, including lowfrequency electrical current pulse stimulation, radio-frequencystimulation, mechanical stimulation, thermal stimulation, visualstimulation and audio stimulation. The control unit uses one or moreoptimization methods to adjust the parameters of each activator, such asthe activator's activation timing, frequency and pattern.

In one aspect of the invention there is provided a neuromodulationsystem for treatment of physiological disorders. The system includes oneor more stimulators for stimulating at least one of the cranial nerves;one or more detectors configured for detecting a predeterminedphysiological state; and a control unit that controls nerve stimulationby the one or more stimulators so that it is synchronized with the atleast one predetermined physiological state detected by the at least onedetector.

In an embodiment of the system, the physiological state is at least onesleep stage. In some cases of this embodiment one or more detectors areconfigured to detect one or more predetermined sleep stages selectedfrom rapid eye movement (REM) sleep or slow wave sleep (SWS) and wherethe one or more stimulators provide stimulation only during the selectedsleep stage. In some cases of this embodiment the one or morestimulators are configured to provide stimulation that is synchronizedwith a predetermined sleep stage so as to provide treatment ofphysiological disorders selected from a group consisting of: Alzheimer'sdisease, sleep disorders, other neurological disorders, and heartpathologies. The heart pathologies are chosen from heart failure andatrial fibrillation. The other neurological disorders are selected froma group of disorders consisting of: Parkinson's disease, tremor,depression, migraine, headache, peripheral pain, attention deficitdisorder (ADD), attention deficit and hyperactivity disorder (ADHD),sleeping disorders, cognitive dysfunctions and sexual dysfunctions.

In some embodiments of the system, the cranial nerve stimulated is thevagus nerve. In some cases of this embodiment, the vagus nerve is theauricular branch of the vagus nerve.

In another embodiment of the system, the one or more stimulators arenon-invasive stimulators positioned at a location selected from thegroup of locations consisting of: behind the ear (BTE) of a patient, inthe ear (ITE) of a patient, in the ear canal (IEC) of a patient, andcompletely in the ear canal (CIC) of a patient.

In other embodiments of the system, the control unit is configured toprovide a feedback mechanism that controls one or more stimulators. Insome cases of this embodiment, the feedback mechanism is selected from agroup consisting of the following mechanisms: feedback mechanism basedon the patient's heart rate; feedback based on a cognitive test result;feedback mechanism based on sleep stage; and feedback based on an EEGparameter.

In yet another embodiment of the system, the system includes a wiredconnection between the one or more detectors, the control unit, a powersupply and the one or more stimulators.

In still another embodiment of the system, the system includes awireless connection to a remote control unit.

In yet other embodiments of the system, the one or more stimulators areat least two stimulators.

In another embodiment of the system, the one or more stimulators are twoor more stimulators each different from the other simulators; eachproviding a different type of stimulation.

In another aspect of the present invention there is provided a method ofneuromodulating a patient for treatment of physiological disorders. Themethod includes the steps of: detecting a predetermined physiologicalstate; and applying stimulation to one of the cranial nerves during thepredetermined physiological state by one or more stimulators of aneuromodulation system.

In an embodiment of the method, the cranial nerve is the vagus nerve. Insome cases of this embodiment, the cranial nerve is the auricular branchof the vagus nerve (ABVN).

In another embodiment of the method, the method further includes a stepof placing one or more stimulators of the neuromodulation system asdescribed above into a patient's ear for stimulation of the ABVN.

In another embodiment of the method, the physiological state is aspecific sleep stage. In some cases of the embodiment, the specificsleep stage is selected from a rapid eye movement (REM) sleep stage or aslow wave sleep (SWS) stage.

In yet another embodiment of the method, the neuromodulation isdelivered for treatment of Alzheimer's disease.

In a further embodiment of the method, the method further includes astep of optimizing the one or more stimulators to provide stimulationfor treatment of physiological disorders selected from a groupconsisting of: Alzheimer's disease, sleep disorders, other neurologicaldisorders, and heart pathologies.

In still another embodiment of the method, the step of applying one ormore stimulators is the step of applying two or more stimulators. In yetanother embodiment, the two or more stimulators are differentstimulators providing different types of stimulation.

Terminology

“Stimulation” and “activation” and words derivative therefrom are usedsynonymously herein unless specifically indicated otherwise. For example“activate” is synonymous with “stimulate” and “activator” is synonymouswith “stimulator”. “Stimulator” when used herein contains all elementsnecessary for stimulation including elements such as the stimulatorelectrodes unless these elements is discussed separately in the text.“Sensor” and “detector” and words derivative therefrom are usedsynonymously herein unless specifically indicated otherwise. For example“sense” is synonymous with “detect” and “sensing” is synonymous with“detecting”.“Pattern” or “stimulation pattern” has been used herein to mean pulseshape (intensity, duration, polarity, tooth shape or square shape etc.),rest times between pulses and modulation thereof (each pulse duration is10% more than previous one, up to 200% and then decreasing by 10% until100%), for example intermittent activation or periodically changing ofone of the stimulation intensities.“Optimization” in the context of this application means setting ofstimulation parameters like frequency or intensity of each stimulator toreceive the strongest response while keeping away from inducing pain tothe patient. If more than one stimulator is used, optimization will meanin addition, finding the best combination of synchronization in time andintensities to activate the stimulators to provide the strongestresponse as detected by the relevant detector,“Optimization methods” in this respect will mean the algorithm to findthe optimal activation parameters, like scanning through each activationparameter while holding the rest fixed, or more efficient algorithmsthat reduces the scan time, for example starting from the strongeststimulation and reducing to bearable pain.

LIST OF FIGURES

The disclosed inventions will be described with reference to theaccompanying drawings, which show important sample embodiments of theinvention and which are incorporated in the specification hereof byreference, wherein:

FIG. 1 is a schematic illustration of one embodiment of a proposedimplanted stimulation system;

FIG. 2 is a schematic illustration of an example of electricalstimulation of a patient's foot;

FIG. 3 is a schematic illustration of an example of electricalstimulation of a patient's back;

FIG. 4 is a schematic illustration of an example of mechanicalstimulation of a patient's foot;

FIG. 5 is a schematic illustration of an example of thermal stimulationof a patient's foot;

FIG. 6 is a schematic illustration of an example of mechanicalstimulation of the carotid artery which in turn activates the carotidbranch of the vagus nerve.

FIG. 7 is a schematic illustration of an example of a wearable controlunit;

FIG. 8 illustrates a block diagram depicting stimulation based onoptimization methods

FIG. 9 is a schematic illustration of a second embodiment of theproposed system;

FIG. 10 is a schematic illustration of third embodiment of the proposedsystem;

FIGS. 11A to 11C show various options for positioning an electrode of astimulator in the ear;

FIG. 12 is a schematic illustration of a fourth embodiment of theproposed system;

FIG. 13 is a schematic illustration of a fifth embodiment of theproposed system which is comprised of electrical activation by VNS usingimplantable stimulator and mask sleep sensor

FIG. 14 is a schematic illustration of a sixth embodiment of theproposed system

FIG. 15 is a specific implementation of a tVNS device for positioningcompletely in ear canal (CIC).

FIG. 16 is a schematic illustration of a seventh embodiment of theproposed system;

FIG. 17 illustrates a block diagram depicting how stimulation isactivated or deactivated from the sleep sensor via wirelesscommunication to the stimulator platform;

FIG. 18 depicts a behind-the-ear stimulation device;

FIG. 19 depicts an in-the-ear stimulation device; and

FIG. 20 depicts a band holding two stimulation means for positioningelectrodes in both ears.

DETAILED DESCRIPTION OF THE INVENTION

The present invention introduces an effective way to deliver one or moreneurological activations for the treatment of neurological disorders.Nerve activators using different activation techniques may be controlledby a single control unit.

Activators that may be used can provide at least one of the followingtypes of stimulation:

-   -   Electrical stimulation may be provided by a wide spectrum of        activators, including sensory nerve activators and/or muscle        activators. A specific example for this invention is stimulation        of the vagus nerve. In a specific embodiment, such activation is        done in an afferent direction, resulting in activation of brain        centers that are linked to the vagus nerve. The stimulation can        be effected by using an implanted nerve stimulator and a        stimulation lead. Electrical nerve stimulation can also be        effected by stimulation of nerves using a non-invasive external        electrical stimulator. Electrical stimulation of muscle can be        effected by activation of limb muscles at a predetermined        frequency and intensity. (See FIG. 2 and description thereof        herein below.) A specific electrical activation embodiment        includes activation of the human foot. Such activation can        trigger both nerve stimulation and muscle stimulation. Another        embodiment of electrical activation is to activate the body at        known locations that are used for acupuncture treatment. Another        nerve stimulation technique which may be used is an external        nerve stimulation technique known as transcutaneous electrical        nerve stimulation (TENS). (See FIG. 3 and description thereof        herein below.) A specific example of such TENS configuration is        stimulation of the auricular branch of the vagus nerve (ABVN)        that is located in the ear of the subject.    -   Mechanical stimulation may be provided by a wide range of        techniques, including pressure stimulation and vibration        stimulation. In a specific embodiment, mechanical stimulation        includes a vibrator that mechanically activates the human        carotid nerve in the neck (see FIG. 6 and description thereof        herein below) which in turn activates the vagus nerve. Another        specific embodiment includes mechanical activation of a human        foot. (See FIG. 4 and description thereof herein below.) Such        activation can be done in specific spots that are normally used        in Shiatsu therapy.    -   Thermal stimulation can be used either for full body activation,        or selected spot activation. Full body activation can include        placing the patient in a controlled temperature environment or a        hot tub. Alternatively, such thermal activation can be applied        to a specific spot on the patient's body. In a specific        embodiment, such activation can be applied to the patient's        foot. (See FIG. 5 and description thereof herein below.) In        another embodiment, the thermally treated spot can be the head        of the patient.    -   Visual stimulation can be effected by presenting light patterns        to the subject. Such light patterns can be alternating light        with a predetermined frequency. It can include known images, for        example, or a sequence of images. In a specific embodiment such        sequence may include images of faces, which may include known        faces or a mixture of known and unknown faces.    -   Audio stimulation can be effected by presenting an audio pattern        to the subject. Such audio pattern may include specific sounds,        both known and unknown. It can include alternating sounds that        are presented at a predetermined frequency. In a specific        embodiment, such audio activation may include playing a musical        piece that is familiar to the subject.    -   Cognitive stimulation is targeting the activation of the brain        to perform cognitive activity such as reading, mathematical        calculation, logic challenges, emotional reaction such as        happiness, and sadness. In a specific embodiment, such        activation may include a questionnaire that the subject should        complete. Another embodiment may include an emotional visual        that can trigger an emotional state in the subject. Cognitive        activation can use tools like an interactive tablet computer        (see FIG. 1 and description thereof herein below) with a        dedicated application that generates cognitive stimulation and        collects responses from the patient.

The control unit of the system can include several communication linksto interact with the one or more activators. Specific examples can bemagnetic activation of an implantable nerve stimulator and remoteactivation of a computer-based cognitive stimulator. Another example ofspecific activation can be simultaneous activation of two or moreseparate implantable devices. These may be similar devices or differentdevices.

Additionally, in some embodiments, the control unit can be configured toinclude power source to power the various activators wirelessly. Aspecific example of wireless powering can be using inductive coupling asan implantable nerve stimulator.

The control unit can be designed to be an external, portable, easy tocarry device that can be attached to the patient's body using a wearableelement. (See FIG. 7 and description thereof herein below.)

Another embodiment of the control unit can include two separate parts:one part that is wearable and contains all the communication links and asecond part that implements the user interface and the algorithms foroptimization methods.

The control unit can use several control algorithms to enhance oroptimize the stimulation effectiveness as described in FIG. 8,including:

-   -   Adaptively based on cognitive response—Stimulation during        specific sleep stages like REM sleep;    -   Inducing specific cognitive state, sadness for example, for best        stimulation effectiveness;    -   A feedback mechanism in which stimulation is imposed in response        to specific phenomena detected by the detector;    -   Close loop adjustments of the stimulation intensity or frequency        in real time in response to detection of cognitive or        physiological parameters;    -   Combined synchronize stimulations from more than one stimulator        to elevate the cognitive effect;    -   Pin point the most effective stimulation timing by combining        reading from more than one detector to find the most effective        timing for stimulation;    -   Adaptively based on EEG patterns, for example, the intensity of        theta waves or other EEG patterns that indicate different sleep        stages;    -   Adaptively based on a subject's physical activity intensity, for        example during rest or exercise periods;    -   Adaptively based on heart rate (HR), for example, during HR        elevation or when the HR is above a set threshold.

An external or internal sleep sensor provides input on the sleep stages.The sleep sensor unit can include several communication links tointeract with an activator. A specific example can be a magneticactivator for providing magnetic activation of an implantable nervestimulator. Another specific activation can be using Bluetooth signalingto a non-invasive tVNS ABVN stimulator.

A specific example of a sleep sensor is an ‘under the mattress’ sleepsensor, using an electro-mechanical sensor, such as a piezo-electricsensor. (See FIG. 16 and description thereof herein below). The sensormay be connected wirelessly to an implantable stimulator. The electrodeof the stimulator is located in the subject's neck and intended tostimulate the vagus nerve (see FIG. 9 and description thereof hereinbelow), or to a non-invasive tVNS stimulator with an electrode attachedto the external ear. (See FIG. 12 and description thereof herein below.)The tVNS circuitry can be located behind the ear, in the ear, or in theear canal. The stimulator can be self-powered, or wirelessly incommunication with an energy source, or in a wired connection with anenergy source.

The tVNS electrodes can be attached to the concha, to the ear canalsurface, or have its electrodes split between the concha/externalauditory canal, and the back of the ear, or both electrodes at the backof the ear. (See FIGS. 11A, 11B and 11C and 18 and descriptions thereofherein below.)

It is to be understood that the embodiments of the electrode hereindescribed are merely illustrative of the application of the principlesof the invention. It will be appreciated that many variations,modifications, among them ones based on ergonomic considerations, toallow comfortable use of the device during sleep, may be made. The earBluetooth unit can have its antenna on a chip, or to be printed orembedded in soft encapsulation.

The stimulation electrode attached to skin near the ABVN can providesurface current pulses through monopolar electrodes, in the form ofsurface current, or through the ear tissue, where one monopolarelectrode is located at the back of the ear at one of ABVN locations,and the other monopolar electrode is at the concha, or in the externalauditory canal.

In some configurations, stimulation can be applied through bothlocations simultaneously using several monopolar electrodes placed inthe concha, in the external auditory canal or in other places inside theear canal, using a reference electrode placed at the back of the ear.

A sleep sensor may be of an eye mask type, a movement sensor or anelectrical signal sensor that can be integrated into the ear stimulator.The sleep sensor may be connected to the ear stimulator via wires or viawireless communication, such as via a Bluetooth connection. (See FIG. 13and description thereof herein below.)

The sleep sensor can use EEG signals measured from the head usingdedicated electrodes. The EEG electrodes can be used for detecting sleepstages and changes in hippocampus activity, for example by monitoringtheta waves.

The device may have all its elements: power source, sleep sensor,control unit, stimulator in a single unit, or have all elements in oneunit except for one of the following: the sleep sensor, the controlunit, or the stimulation electrodes.

In some cases, the stimulator can be placed simultaneously in both ears.(See FIG. 20 and description thereof herein below.) In such a case,stimulation can be done simultaneously, or separately. The system mayinclude a heart rate (HR) monitor that may enable closed loop evaluationwith any of the stimulation parameters, including time of activation,frequency and intensity. In a specific embodiment, if the HR monitordetects reduction in heart rate by more than a preset value due tostimulation it stops or reduces the stimulation intensity until theeffect of activation is reduced below the preset value. Such presetvalue can be any value between 1 beat per minutes (BPM) and 10 BPM.

Optimization can mean in one embodiment (see FIG. 1 and descriptionthereof herein below) reacting to the patient input as sensed throughthe answers the patient gives to the tablet questionnaire. When thepatient is in a specific cognitive state, sadness for example, thestimulation will be activated.

Cognitive stimulation using tVNS excitation (see FIGS. 10 and 14 anddescription thereof herein below) or other cranial nerve stimulation canbe synchronized to perform stimulation at the same time that the brainperforms cognitive activity such as reading, mathematical calculation,logic challenges, and/or undergoes emotional reactions such ashappiness, and sadness.

In a specific embodiment such activation may include a questionnairethat the subject should answer. Another embodiment may include showingan emotion inducing picture that can trigger an emotional state in thesubject. The cognitive activation can use tools such as an interactivetablet computer with a dedicated application that generates cognitivestimulation and collects responses from the patient. (See FIG. 1 anddescription thereof herein below.)

Sensory stimulation such as music can be added simultaneously with tVNSactivation or other cranial nerve stimulation. Such activation can beinitiated during specific sleep stages. In a specific embodiment, suchaudio activation may be by playing music that is familiar to thesubject.

Additionally, in some embodiments, the control unit can include a powersource for powering the stimulator to which it is in wirelessconnection. A specific example can be powering the activator wirelesslyby using inductive coupling.

The tVNS stimulation or other cranial nerve stimulation may be used forimproving the quality of sleep. Specifically, this can be affected byinducing additional periods of REM sleep or by prolonging the REM sleepperiods when they occur.

Sensory stimulation such as music or smell can be added simultaneouslyusing tVNS activation while the user is awake.

The control unit can use one or more of the following optimizationmethods to adjust the stimulation's timing/synchronization, intensityand patterns. (See FIG. 8 and description thereof herein below.):

-   -   Adaptively based on cognitive response potency    -   Stimulation during REM sleep periods or during other types of        sleep stages such as slow wave sleep (SWS)    -   Adaptively based on EEG patterns    -   Adaptively based on physical activity intensity    -   Adaptively based on heart rate

The tVNS stimulation unit can be made of soft materials which enables itto be inserted into an ear with minimal effect on the subject's sleep.The tVNS stimulation unit can be a type of device located behind the ear(BTE), in the ear (ITE), in ear canal (IEC), or completely in ear canal(CIC), as in FIGS. 11A, 11B, and 11C and FIG. 18 (see descriptionsthereof herein below), or any combination of these. It may include morethan one stimulation electrode. The device may include a control unitthat can select the most efficient electrode set based on stimulationparameters for each specific sleep stage.

The CIC type device can be made of three units (see FIG. 15 anddescription thereof herein below), the stimulating section with itselectrodes, wireless connection section and a battery. The device mayhave an arm, to assist insertion and removal of the device from the earcanal. The ear neuromodulation platform has an internal structure, withelastic spacers between its components. It may have a form orarrangement of its components, e.g. of the battery, stimulator andwireless communication, and its encapsulation that allows it to conformwith, or be adjustable to, the ear anatomy, in particular to the varyinganatomical cross-section of the ear canal. (See FIG. 19 and descriptionthereof herein below.).

The ear unit has a means to adjust the properties of the stimulationwaveform, such as the amplitude of the pulses, via programming of thecontrol unit. The control unit can be accessed for parameter setting,with no contact to stimulator's circuitry or using a port forprogramming or having embedded potentiometers with access to adjustingtool such as screwdriver.

Control of activation parameters can be affected using remote controlfrom an external device. The activation parameters, such as electricalcurrent pulse amplitude, can be re-adjusted based on the patient'sfeedback and also by using a cognitive test to evaluate the cognitionpotency. Alternatively, it can be readjusted based on the sleepparameters such as the duration of the REM sleep stage.

An embodiment of the proposed system is comprised of electricalactivation by the tVNS platform using a non-invasive stimulator and asensor under or in a sleep mattress, with a Bluetooth communication linkincorporated into both, as shown in FIG. 16. (See description thereofherein below). Its schematic operation is diagramed in FIG. 17 (seedescription thereof herein below).

All device types, including BTE, ITE as seen in FIGS. 11A, 11B and 11C,or standalone CIC type shown in FIGS. 15 and 19, may have a hole in themiddle for minimal sound blockage and equalized air pressures.

The stimulation electrodes can be made of metal contacts shaped tooptimally provide the electrical or heat pulses. They can be made of, orcoated with, conductive adhesive material or conductive fabric.

There can be electrodes placed in both ears (see FIG. 20 and descriptionthereof herein below.), where the electrodes can be used for sensing andstimulation. The electrodes can be connected wirelessly or by wires andcan measure the electrical potential difference between the two ears. Insuch a case, the configuration may include a band that is placed at theback of the neck and at the forehead, or only at the back of the neck,or over the head or with a hat net.

The simulation can be applied in conjunction with or in relation to drugadministration, in such way that the stimulation is synchronized withdrug intake, or during the time when it is active. Nerve stimulation canenhance or suppress release of chemicals by the brain, such asneurotransmitters, in a timely manner with regard to drug activity.

An embodiment of this invention includes a neuromodulation platform fortreatment of neurological disorders comprising: a sensor measuring theparameters of specific body action; at least one nerve activator; and acontrol unit synchronizing the nerve activator to the body actions.

The nerve activator can be one of the following stimulators:

-   -   Electrical stimulator    -   Mechanical stimulator    -   Thermal stimulator    -   Visual stimulator    -   Audio stimulator    -   Cognitive stimulator

In a specific embodiment, the neuromodulation includes at least threeactivators.

In some embodiments, the electrical stimulation is stimulation of thevagus nerve using an implantable stimulator.

In some embodiments, the control unit of the stimulator includes anon-implantable magnetic wand that communicates with the implantablevagus nerve stimulator.

The apparatus described above may also include a second stimulator thatprovides cognitive stimulation. The cognitive stimulator described abovemay also comprise a computerized viewer that is controlled by thecontrol unit.

In some embodiments, the nerve activator can be implemented in one ofthe following platforms:

-   -   A completely implantable device    -   A device including an external control unit and an implantable        activator    -   A device that is in direct contact with the treated subject's        skin    -   A device with a control unit that is not in contact with the        subject being treated and an activator that is in direct contact        with the treated subject skin    -   A device that is totally not in direct contact with the treated        subject        In some embodiments, the control unit for treatment of        neurological disorders includes:    -   A processing unit; and    -   At least one communication module, each module in communication        with a separate nerve activator.        The communication modules described above may perform        communication through one of the following techniques:    -   Magnetic field transmission    -   Electrical field transmission    -   Optical transmission    -   Wireless transmission    -   Wire electrical transmission    -   Electrical stimulation    -   Mechanical stimulation    -   Thermal stimulation    -   Visual stimulation    -   Audio stimulation    -   Cognitive stimulation

The control unit described above may include a cognitive sensor forsensing cognitive markers or physiological signals.

The control unit described above may include an adaptive controlmechanism that can change the parameters of the activator based on aninput from the cognitive sensor. The control unit described above mayinclude an eye tracking sensor that detects the onset of rapid eyemovement periods during sleep.

The control unit described above may include a cognitive sensor thatdetects the intensity of cognitive activity and synchronizes theactivator to apply stimulation during a period of high cognitiveactivity.

In some embodiments, the processor that is connected to a control unitthat is used for treatment of neurological disorders includes a datarecording means that records at least one of the following inputs:

-   -   The parameters of the activator    -   The cognitive intensity as measured by EEG sensors or cognitive        questionnaire    -   Physiological signals such as heart rate, onset and termination        of REM sleep periods, EEG, activity sensor, body temperature and        bio-impedance

The processor of the control unit described above may include ananalyzer to perform multi-parameter analysis of the patient conditionduring treatment and during time between treatments.

The current invention also relates to a neuromodulation platform fortreatment of neurological disorders comprising: at least two parallelbrain activators as shown in FIG. 8. and a control unit that controlsthe activation parameters and synchronizes the multiple activationprocesses

In some embodiments, the brain activation processes involves one of thefollowing types of cognitive stimulations: audio, cognitive challenge,such as reading, solving puzzles, logic tasks and emotional challenge,such as experiencing happiness, fear or an excitement. In someembodiments, the neuromodulation platform comprises a vagus nervestimulator and a detector for detecting sleep stages

In some embodiments, the neuromodulation platform is configured todetect REM sleep and provide stimulation only during REM sleep periods

In some embodiments the neuromodulation platform includes an earstimulation platform to stimulate the auricular branch of the vagusnerve (ABVN).

In some embodiments, the neuromodulation platform is configured toaffect concentrations of bio-chemicals in the brain, such as proteinsand neurotransmitters.

In some embodiments, the neuromodulation platform is configured toprovide stimulation that is synchronized with sleep stages and to treatphysiological disorders such as Alzheimer's, sleep disorders,neurological disorders and heart pathologies such as heart failure andatrial fibrillation

In some embodiments, the ear stimulation platform comprising anon-invasive nerve activator includes one of the followingconfigurations: an activator located behind the ear (BTE); an activatorlocated in the ear (ITE); an activator located in the ear canal (IEC);and an activator located completely in the ear canal (CIC).

In some embodiments, the ear stimulator comprises at least one set ofradial anode and cathode electrodes placed at the ear canal.

In some embodiments, the ear stimulation platform comprises an ear canalpart with a middle core that enables sound transmission.

In some embodiments, the middle core can be an open void.

In some embodiments, the ear stimulator comprises an internal structureand encapsulation that allows it to conform to, or be adjustable with,the ear anatomy

In some embodiments, the ear stimulator includes a sound generator.

In some embodiments, the neuromodulation platform includes two earstimulators, one placed in the right ear and one in the left ear (SeeFIG. 2 and description thereof herein below)

In some embodiments, the neuromodulation platform comprising two earstimulators one for each ear, that have a connecting wire. In someembodiments, the neuromodulation platform comprises a feedback mechanismthat controls the stimulation.

In some embodiments, the feedback mechanism is selected from one of thefollowing mechanisms: feedback mechanism based on heart rate; feedbackmechanism based on EEG parameters measured by EEG electrodes; andfeedback mechanism based on cognitive test results.

In some embodiments, the neuromodulation platform comprises anelectrical signal sensor and an ear stimulator.

In some embodiments, the neuromodulation platform comprises a stimulatorfor stimulating the auricular branch of the vagus nerve and furthercomprising at least one anode and at least one cathode electrode thatare in direct contact with the skin of an ear of the subject.

In some embodiments the neuromodulation platform comprising at least oneelectrode placed in one of the following locations selected from thegroup of locations consisting of: the back of the ear, the concha andthe ear canal.

In some embodiments the neuromodulation platform comprises a sleepsensor in electrical communication with a processing unit and acommunication module. The sleep sensor may detect at least one of thefollowing parameters: onset of rapid eye movement during sleep, EEGsignal, body activity, and heart rate.

In some embodiments, the neuromodulation platform may have a controlunit that adjusts the amplitude of the stimulation pulses, using anadjustable potentiometer.

In some embodiments, the neuromodulation platform is a platform forpromoting drug administration having a stimulator for stimulating theauricular branch of the vagus nerve. The platform comprising: an earcanal stimulation electrode of the stimulator; a drug delivery systemfor delivering a drug; and a control unit for synchronizing nervestimulation with the timing of drug administration.

In some embodiments, the drug delivery system is adapted for deliveringinsulin.

In some embodiments, the drug delivery system is adapted for deliveringdrugs that are targeting the central nervous system

In some embodiments, the drug delivery system is adapted for deliveringdrugs for treatment of cardiac pathologies

In some embodiments, the drug delivery system is adapted for deliveringdrugs for treatment of cancer

In an embodiment, a neuromodulation platform for treating ADD or ADHD,the platform comprises:

an EEG detector for measuring an EEG signal;

a control unit establishing ADHD functional status using an analysis ofthe EEG signal;

a stimulator for stimulation of the auricular branch of the vagus nerveof the subject; and

a control unit that adjusts the stimulation parameters of the stimulatorbased on the established ADHD functional status.

In an embodiment, a neuromodulation platform for treating depression,the platform comprising:

an EEG detector for measuring an EEG signal;

a detector for determining a depression status using EEG signalanalysis;

a stimulator of the auricular branch of the vagus nerve of the subject;and

a control unit that adjusts the stimulation parameters for thestimulator based on the determined depression status.

It should be noted that there is a standard depression status ladder anddepression level is assessed accordingly.

In an embodiment, a neuromodulation platform for treating migraines, theplatform comprising:

an EEG detector for measuring an EEG signal;

a controller for determining a migraine status using an analysis of theEEG signal;

a stimulator for stimulation of the auricular branch of the vagus nerveof the subject;

and;

a control unit that adjusts the stimulation parameters of the stimulatorbased on the detected migraine status.

Electrical stimulators when electrical stimulation is used may beselected from among the following:

-   -   Current control stimulator    -   Voltage control stimulator    -   Charge control stimulator    -   Monophasic stimulator    -   Dual phase stimulator    -   Multiphase stimulator    -   Single polarity stimulator    -   Dual polarity stimulator        The above list is not intended to be an exhaustive list.

The stimulators or detectors listed above may use different electrodesto deliver the stimulation or sense physiological parameters like EEG orECG, such as:

-   -   Capacitance electrode (nonconductive) for optimal biological        interface assuring no electrons pass to the biological        ion-charge system    -   Conductive electrode enabling delivery of larger charges in        specific time intervals    -   Hybrid electrode, mostly capacitance with a residual of        conduction, may be used as a compromise between the two prior        types    -   Mono-polar electrode can be used for better charge delivery,        that is maximum usage of electrode area to deliver the same        polarity    -   Bi-polar electrode to enable better stimulation localization    -   Reference electrode serving as grounding for most stimulation        devices    -   Dual-use electrode, for both sensing and stimulation. This        requires high capacitance and high isolation between the sensing        and stimulation functions    -   Implantable nerve electrode will be warping the target nerve to        increase the contact area and ensure good contact for long time        periods.    -   Wet electrode refers to an electrode with conductive hydrogel        placed on top of it to improve conduction (decrease the        resistance) between the electrode and the subject's skin or        other organ.    -   Dry electrode refers to an electrode that has a good skin        interface and doesn't require a conductive hydrogel.        It should be apparent to persons skilled in the art that the        stimulator electrodes used may be different from the sensing        electrode used by detectors, also sometimes denoted herein as        sensors, like EEG or ECG.

Detectors usable in the systems described herein may include thefollowing:

-   -   EEG sensors containing at least two electrodes up to as many as        16 electrodes. These sensing electrodes can be dry or wet type        electrodes.    -   ECG sensor or heart rate sensor to sense heart rate and other        heart events like tachycardia or other heart conditions. This        sensor may be implemented by a photoplethysmography (PPG)        sensor, or surface ECG sensor or implantable ECG sensor.    -   Sleep sensor to monitor and differentiate sleep stages like REM        or SWS. Sleep sensor may include ‘under the mattress sensor’,        wearable sensor like watch type or remote sensor like desktop        sensor. The sleep sensor may be based on technology like        electro-mechanical sensor, such as a piezo-electric sensor, or a        micro electro-mechanical system (MEMS) accelerometer.    -   Motion sensor or actimetry sensor to monitor the activity        intensity of the patient, like laying, seating, standing,        walking etc.    -   Breathing sensor to monitor the subject's breathing function.    -   Eye tracking sensor may be used to distinguish sleep conditions        like REM sleep or awake conditions like reading

Cognitive stimulators may include: computer base stimulator like tablet,desktop, television, or smartphone. These devices may or may notinteract with the patient. They may stimulate visual, audio and othersenses in two dimension or three. These devices may implement virtualreality or augmented reality to stimulate the patient. Cognitivestimulation may require the patient to preform one or more of thefollowing activities: reading, watching, answering a questionnaire,listening, orientating in 2-dimensional or 3-dimensional space. Specificstimulation can focus on different brain activities like mathematicalproblems, memory challenges, verbal tasks, visual tests, gross motoricfunctions or fine motoric functions, and more.

Mechanical stimulators apply local pressure in different frequencies.Low frequency (up to 2 Hz) will feel like a pressure wave to thepatient, and medium frequency (2 to 30 Hz) will feel more likevibrations. High frequencies (more than 30 Hz) are hard to feel directlybut still may have nerve stimulation effects. The mechanical stimulatorwill require a mediator, like muscle, limb, or artery to stimulate anadjacent nerve and evoke a brain response. For example, massage (lowfrequency pressure wave) of the carotid artery is known to affect thecarotid branch of the vagus nerve and induce unconscious.

Thermal stimulators apply local heat or cold at specific spots on thebody or to a whole organ. The stimulation effect, mediated by biologicaltissue like skin or tooth, to the nervous system conveys the sensed heator cold to the brain. Thermal stimulation like feeling cold may heightenthe patient's sensing, improving other stimulation effects, for examplecognitive or electrical effects when the two stimulations are applied intime synchronization.

Audio stimulators carry sound to a patient's ear through the air or bydirect bone conduction. Audio stimulation is known to induce modechanges in a patient which in turn may enhance a patient's sensitivityto cognitive or electrical stimulation.

A therapeutic method is describe herein intended to treat aphysiological disorder from the list of: Alzheimer's Parkinson's,tremor, depression, migraine, headaches, peripheral pain, attentiondeficit disorder (ADD), attention deficit and hyperactivity disorder(ADHD), sleeping disorders, cognitive dysfunctions, arterialdefibrillation and sexual dysfunctions.

The method consists of stimulating cranial nerves, often, but withoutintending to limit the invention, the vagus nerve at specificphysiological states to elicit a best therapeutic effect. Somephysiological states comprise relevant events for therapy in each of theabove disorders, for example, elevated cognitive state enhances vagusnerve stimulation (VNS) effect on cognition. Accordingly, by detectingthe specific elevated cognitive states and applying VNS at this specifictime, cognition rehabilitation may occur. An elevated cognition statecan occur while the patient is sleeping (REM sleep) or while awake (inan intense cognitive challenge state).

The method may control the stimulation based on reading of physiologicalstate detectors, like a motion detector, a brain activity detector suchas an electroencephalograph (EEG) detector, a heart rate detector suchas electrocardiogram (ECG) and others. The method may adjust stimulationto occur at specific times based on the physiological detectors therebyproducing the best cognitive effect. Furthermore, the method may adjustin real time the stimulation intensity or frequency to reflect thephysiological detector reading representing the patient's physiologicalstate.

A special physiological state of therapeutic interest is sleep where thetherapy can be administered to the patient with minimal discomfort.During sleep several distinguishable cognitive states like REM sleep orslow wave sleep (SWS) affect specific brain areas. A methodadministrating stimulation in conjunction with these states may resultin cognitive rehabilitation. The described method can use noninvasiveVNS or transcutaneous VNS (tVNS) simplify therapy administration andallow its use for the general population. More specifically, it allowsfor treatment of patients in moderate condition (which preclude themfrom invasive solutions) or those which cannot undergo invasive surgery.tVNS can be applied to two main locations, the carotid branch and theauricular branch of the vagus nerve. The auricular branch (ABVN) isbetter suited for prolong administration of therapeutic device describedin this method.

DETAILED DESCRIPTION OF FIGURES

The following description should be read in conjunction with theDescription of the Invention that appears above.

The numerous innovative teachings of the present application will bedescribed with particular reference to presently preferred embodiments(by way of example, and not of limitation). The present applicationdescribes several inventions, and none of the statements below should betaken as limiting the claims generally. Where block diagrams have beenused to illustrate the invention, it should be recognized that thephysical location where described functions are performed are notnecessarily represented by the blocks. Part of a function may beperformed in one location while another part of the same function isperformed at a distinct location. Multiple functions may be performed atthe same location.

FIG. 1 depicts a schematic illustration of one embodiment of theproposed system which comprised of electrical activation by VNS usingimplantable stimulator (1), an interactive tablet computer (12) forcognitive stimulation, and a wearable control unit (3). A patientimplanted vagus nerve stimulation system (1) including vagus nerveelectrode (2) which is attached to the vagus nerve. The vagus nerveelectrode (2) is connected to the nerve stimulator (1) by a flexiblelead (31). An external wearable control unit (3) is worn as a necklaceon the neck and placed close to the nerve stimulator (1) to enablecommunication between the control unit and the nerve stimulator. Thecontrol unit (3) can be placed in proximity of the implantablestimulator using a vest, a belt or a sticker. The control unit which cancontrol wirelessly one or more activation means as illustrated in theother figures synchronizes the VNS stimulation with the otherstimulation mean(s) and synchronize timing and intensities of the VNSstimulation to the other stimulation mean(s) parameters.

FIG. 2 illustrates a specific embodiment of an external electricalstimulation system to the foot of a patient. Electrodes (5) are attachedto the foot of the patient and connected to stimulation generator (4)via connecting wires (32). The electrodes may be disposable or reusableand may be self-adhesive or otherwise attached to the foot.Additionally, the electrode may be implemented in footwear andaccessories to footwear such as shoes, socks and stockings. Thestimulation generator is connected wirelessly or via wires to a controlunit (not shown in this Figure) and may be internally or externallypowered.

FIG. 3 illustrates another embodiment of external electrical stimulationusing TENS (Transcutaneous Electrical Nerve Stimulation). A TENS unit(7) that comprise of electrodes and a stimulation generator is attachedto the patient back. The TENS unit is controlled wirelessly or viaconnection wires by a control unit (not shown in this Figures). In theinstant embodiment, another stimulator, an interactive tablet computer(6), is illustrated, which generates cognitive stimulation targeting theactivation of the brain to perform cognitive activities such as reading,mathematical calculation, logic challenges, and emotional reactions suchas happiness, and sadness.

FIG. 4 illustrates a specific embodiment of mechanical stimulation tothe foot of a patient. A wearable footwear device (9) is used togenerate pressure or vibrations at specific locations of the foot,thereby stimulating nerves. The properties of the mechanical pressure orvibration stimuli, such as intensity, frequency and activation patternare controlled wirelessly or via connection wires by the control unit(not shown in this drawing). This mechanical stimulation can beactivated in time and intensity so that it is synchronized with otherstimulation methods such as like electrical stimulation, or cognitivestimulation. The dual stimuli enhance the brain's response so that isgreater than a reaction to a single stimulus.

FIG. 5 illustrates a specific embodiment of thermal stimulation to afoot of a patient. A thermal device (10) is used to generate heat orcold at specific locations of the foot to stimulate specific footnerves. Specific requirements, such as the heating locations andtemperature, are controlled wirelessly or via connection wires by acontrol unit (not shown in this Figure). The control unit can beintegrated within the stimulation device (10). Thermal stimulation canbe activated in time and intensity so that it is synchronized with otherstimulation methods such as mechanical stimulation, electricalstimulation, or cognitive stimulation to produce a brain responsegreater than a reaction elicited by a single type of stimulation. Thestimulation device (10) can be an integrated stimulation device thatuses both thermal and mechanical (pressure or vibration) stimulationsfor greater therapeutic effect.

FIG. 6 illustrates another embodiment of the placement of a mechanicalstimulator. The wearable vibrator (8), the stimulator, is positioned tobe worn on the patient's neck. The stimulator generates mechanicalvibration to stimulate the carotid artery, which in turn stimulates thecarotid branch on the vagus nerve in the patient's neck. Properties ofthe mechanical vibration, such as intensity, frequency and pattern, arecontrolled wirelessly or via connection wires by the control unit (notshown in this Figure). The mechanical stimulation can be activated intime and intensity synchronization with other stimulators, such aselectrical and thermal stimulators.

FIG. 7 illustrates another embodiment of a wearable control unit (11)that is implemented as a watch. In this embodiment, the control unit(11) can control the stimulator wirelessly and can include an internalcommunication means to control implantable devices by placing thecontrol unit near the implantable stimulator. This wireless control unit(11) can control one or more stimulators of the same type (electricalstimulators) or of different types (an electrical stimulator withmechanical stimulator).

With reference to FIG. 8, a simplified block diagram illustrates astimulation optimization method based on feedback mechanism used withthe systems described herein. One or more detectors (102) senses (111)the patient's (101) condition at a specific time and alerts (112) thecontroller (103) to activate (113) one or more stimulators (104) toalter the patient condition (114).

The patient (101) receives different stimulations (114) from differentstimulators (104). The stimulators (104) can be one or more from thelist of: electrical stimulator, mechanical (pressure or vibration)stimulator, cognitive stimulator (an interactive computer, tablet orsmartphone), thermal stimulator (heat), audio stimulation, and more. Asingle stimulator of the same kind or more than one of the same kind maybe applied.

A control unit (103) orchestrates the stimulation by defining timing,intensity and pattern of each stimulator (104) by direct communication(113) with each stimulator. Control unit (103) may be integrated withother parts of the system or stand alone. The communication (113 and112) of the control unit may be wired to the system's stimulators anddetectors or this could be affected in a wireless configuration.

The detectors (102) may include one or more detectors from the list of:brain activity detector like EEG, heart rate detector like ECG,breathing detector, motion detector, sleep detector, eye trackingdetector, cognitive detector like tablet interacting with the patient,etc. Each specific detector or sensor (102) will sequentially measureattributes of the specific measured parameters and report (112) themdirectly to the control unit (103) to decide on the appropriatestimulation (114) by the dedicated stimulator (104).

The special close loop sensing and stimulation method illustrated inFIG. 8 enables various modes of operation like:

-   -   1. Stimulation in specific cognitive state of the patient, like:        vagus nerve stimulation (114) by implanted vagus nerve        stimulator (104) during REM sleep stage as detected by sleep        sensor (102). This combination enhances the effect of the        electrical vagus nerve stimulation as the brain is starving for        neurotransmitters at REM sleep stage and the VNS may provide        them.    -   2. Inducing a specific cognitive state, for example, sadness, by        a cognitive stimulator (104) such as a sad movie. Then detecting        the intensity of the cognitive state by a cognitive detector        (102) and if the intensity is above a predetermined value,        activating mechanical carotid stimulator (104) which affects the        vagus nerve and induces an enhanced brain response.    -   3. A feedback mechanism in which a noninvasive electrical vagus        nerve stimulation (104) is imposed to enhanced the patient        memory. Control unit (103) receives (112) readings of an EEG        sensor (102) reading that detect theta waves intensity (111) can        adjust the stimulator (104) to enhance the stimulation affect        and consolidate the memory of the patient in a more efficient        way.    -   4. Closed loop adjustments in real time the stimulation (114) to        the activity intensity as measured by specific detector (102).        For example, controlling a thermal stimulator (104) to stabilize        heart rate (HR) as measured (111) by an ECG sensor (102). In        this case, the control unit (103) receives (112) frequent        readings from HR (102) and dynamically adjusts (113) the thermal        stimulator (104). The combined effect of the closed loop        stimulation response teaches the patient to better control the        HR under various conditions.    -   5. Combined synchronized stimulations from more than one        stimulator (104) can enhance patient therapy. For example, the        control unit (103) activates (113) sound stimulation (114) by an        audio system (104) which can induce happiness in the patient and        if at the same time or at some time delay (both herein denoted        as synchronization) an electrical stimulator (104) is activated        (113) so that the system can more effectively treat depression        in the patient.    -   6. Pin pointing the most effective stimulation timing by        combining readings (111) from more than one detector (102) may        intensify the therapy effect of this stimulation. For example, a        sleep detector (102) may provide a general time of a specific        sleep stage, but combining it with an eye tracking sensor (102)        will allow pin pointing the exact time of onset of REM stage        sleep, which in turn is the most sensitive time for VNS        stimulation (114) as the brain is starving for neurotransmitters        at this time. VNS stimulation induces the brain to release        neurotransmitters and at the onset of REM sleep it may intensify        memory consolidation.

It should be noted that a combination of the stimulation controlmechanisms can be used involving more than one sensor or detectorenabling stimulation control based on a combination of body conditions,for example elevated heart rate (measured with ECG) while walking(measured with an activity sensor) or REM sleep (measured by a sleepdetector combined with an EEG sensor).

FIG. 9 depicts a schematic illustration of one embodiment of theproposed system which comprised of electrical stimulation by VNS usingimplantable stimulator (1), and sleep sensor (13) for triggering thestimulation. A patient has an implanted vagus nerve stimulation system(1) so that the vagus nerve electrode (2) is attached to the vagusnerve. The vagus nerve electrode is connected to the nerve stimulator(1) by a flexible lead (31). A sleep sensor unit (13) may be placedunder the mattress, close to the nerve stimulator to enable wirelesscommunication (23) between the control unit and the nerve stimulator.The control unit can be embedded in the sleep sensor (13) or separatelylocated. The sleep sensor (13) can be placed in proximity of theimplantable stimulator using a vest, a belt or a sticker. In addition,the control unit can control wirelessly or through wire communicationone or more activation or monitoring means, like music player or heartrate recorder.

FIG. 10 illustrates specific embodiment which comprised of electricalactivation by tVNS using non-invasive ear stimulator (14) behind theear, while electrode (15) is attached to external ear Concha or earcanal, and sleep sensor (13) for triggering the stimulation. A patienthas a miniature system so that the vagus nerve electrode (15) isattached to the auricular branch of the vagus nerve. A sleep sensor unit(13) is placed under the mattress, close to the nerve stimulator toenable wireless communication (23) between the control unit whichembedded in the sleep sensor (13) and the nerve stimulator.

FIGS. 11A to 11C illustrate other possible embodiments of the proposedtVNS electrode location where the ABVN presence or supply is prominent:like electrode attached to the Concha (16), or to the wall of theexternal ear canal (17), or attached to the back of the ear (18), orhave its poles spilt between said locations, or attached to multipliedlocations. The electrode shape will be such to maximize the tVNSefficiency per location.

FIG. 12 illustrates an embodiment of using a mask sleep sensor (19) witha tVNS stimulator integrated into it (20). In the Figure the tVNSelectrode is shown as originating from the mask belt.

FIG. 13 illustrates another specific embodiment of a mask sleep sensor(19) with the invasive VNS stimulator (1) is triggered by sleep mask(19) via Bluetooth communication (23).

FIG. 14 depicts a schematic illustration of yet another embodiment ofthe proposed system. The system provides electrical activation by tVNSusing a non-invasive stimulator (14), an interactive tablet computer(12) for cognitive stimulation and cognitive detection, and a wearablecontrol unit (3). The electrode (15) is attached to external ear Conchato stimulate the ABVN.

FIG. 15 depicts a schematic illustration of one embodiment of theproposed system. The Figure shows a completely-in-canal (CIC) type ofdevice which is made of three units: a stimulating section (14) withelectrodes (15), a wireless connection section (21) and a battery (22).The soft encapsulation (45) of device (41) has an arm (20) to assistwith the insertion and removal of the device (41) from the ear canal.

FIG. 16 illustrates another embodiment which generates electricalactivation by tVNS. The system comprises a non-invasive behind the earstimulator (14) triggered by sleep sensor (13). The tVNS stimulatorelectrode (15) is attached to external ear concha or ear canal, so thatthe auricular branch of the vagus nerve is stimulated. The sleep sensorunit (13) is placed under the mattress, close to the nerve stimulator(14) to enable wireless communication (23, 24) between the control unitembedded in the sleep sensor (13) and the nerve stimulator (14). Sleepsensor (13) can be placed in proximity to the implantable stimulatorusing a vest, a belt or a sticker. The sleep sensor can controlwirelessly one or more stimulators or monitors, such as a music playeror a heart rate recorder.

FIG. 17 depicts a block diagram where patient (101) stimulation isactivated or deactivated by a stimulator platform (36) controlled by acontrol unit (35) based on sleep sensor (13). Detection is reported viawireless communication. Also shown is an electro-mechanical tuning screwhead (25) which tunes the pulse amplitude or frequency of the stimulatorbased on the patient's reported comfort level.

FIG. 18 shows an exemplary behind-the-ear tVNS stimulation device (27),within a soft material encapsulating (20) body. The electrodes contact(30) is placed on the ear canal wall. A hole (26) allows minimal soundblockage and pressure balancing. The electrode base (28) fits the earconcha to allow for patient comfort and the mechanical stability of thedevice. Also shown is an electro-mechanical tuning screw head (25) tomodify the pulse amplitude based on the reported comfort of the patient.Ear stimulator (27) may also incorporate an audio stimulator which willactivate a speaker within the hole (26). The audio stimulator will beactivated in synchronization with the tVNS electrical stimulator toenhance the combined therapeutic effect.

FIG. 19 depicts an in-the-ear type tVNS stimulation device, with a hole(26) in its body to allow minimal sound blockage and pressureequalization. The device body base (28) is shaped to fit the ear conchato allow patient comfort and the mechanical stability of the device.

FIG. 20 depicts a headband containing a tVNS simulation device, andpotentially a sleep sensor with electrodes (15) placed in both ears.Electrodes (15) can be used for both sensing and stimulation. Theelectrodes are connected and measure the electrical potential differencebetween the two ears for basic EEG analysis. For these functions andadditionally for mechanical stability, a supporting band (29) is placeat the back of the head and at the forehead.

It is to be understood that the embodiments of the invention hereindescribed are merely illustrative of the application of the principlesof the invention. While the invention has been described with respect toa limited number of embodiments, it will be appreciated that manyvariations, modifications and other applications of the invention may bemade.

The invention claimed is:
 1. Neuromodulation system for treatment ofphysiological disorders comprising: at least one stimulator forstimulating a cranial nerve; at least one detector configured fordetecting a predetermined physiological state; and a control unit thatcontrols nerve stimulation by the at least one stimulator so that it issynchronized with the at least one predetermined physiological statedetected by the at least one detector, wherein the predeterminedphysiological state is rapid eye movement (REM) sleep and the at leastone stimulator provides stimulation only during the REM sleep.
 2. Thesystem according to claim 1 wherein the at least one stimulator isconfigured to provide stimulation that is synchronized with the REMsleep so as to provide treatment of Alzheimer's disease.
 3. The systemaccording to claim 1 wherein the cranial nerve stimulated is the vagusnerve.
 4. The system according to claim 3 wherein the vagus nerve is theauricular branch of the vagus nerve.
 5. The system according to claim 4wherein the at least one stimulator is a non-invasive stimulatorpositioned at a location selected from the group of locations consistingof: behind the ear (BTE) of a patient, in the ear (ITE) of a patient, inthe ear canal (IEC) of a patient, and completely in the ear canal (CIC)of a patient.
 6. The system according to claim 1 wherein the controlunit is configured to provide a feedback mechanism that controls the atleast one stimulator, and wherein the feedback mechanism is feedbackbased on a cognitive result.
 7. The system according to claim 6 whereinthe system includes a wired connection between the at least onedetector, the control unit, a power supply and the at least onestimulator.
 8. The system according claim 7 wherein the system includesa wireless connection to a remote control unit.
 9. The system accordingto claim 8 wherein the at least one stimulator is at least twostimulation sites.
 10. The system according to claim 9 wherein the atleast two stimulation sites are each different stimulators eachproviding a different type of stimulation.
 11. A method ofneuromodulating a patient for treatment of physiological disorderscomprising the steps of: detecting a predetermined physiological state;and applying stimulation to a cranial nerve during the predeterminedphysiological state by at least one stimulator of a neuromodulationsystem, wherein the physiological state is a rapid eye movement (REM)sleep.
 12. A method according to claim 11 where the cranial nerve is thevagus nerve.
 13. A method according to claim 12 where the cranial nerveis the auricular branch of the vagus nerve (ABVN).
 14. A methodaccording to claim 11 further comprising a step of placing at least onestimulator of the neuromodulation system onto a patient's ear fornoninvasive stimulation of the ABVN.
 15. The method according to claim11 wherein said neuromodulation is delivered for treatment ofAlzheimer's disease.
 16. The method according to claim 11, furthercomprising a step of optimizing the at least one stimulator to providestimulation for treatment of Alzheimer's disease.
 17. The method ofclaim 11 wherein said step of applying the at least one stimulator is atleast two stimulation sites.
 18. The method of claim 17 wherein the atleast two stimulation sites are different stimulators providingdifferent types of stimulation.
 19. Neuromodulation system for treatmentof physiological disorders comprising: at least one stimulator forstimulating a cranial nerve; at least one detector configured fordetecting a predetermined physiological state; and a control unit thatcontrols nerve stimulation by the at least one stimulator so that it issynchronized with the at least one predetermined physiological statedetected by the at least one detector, wherein the predeterminedphysiological state is rapid eye movement (REM) sleep and at least onestimulator provides stimulation only during the REM sleep, wherein thephysiological disorder is Alzheimer's disease.